Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as the collagenases, stromelysins and gelatinases (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. It has been found that hydroxamic acid MMP inhibitors can also inhibit the production of the cytokine tumour necrosis factor ("TNF"). Compounds which inhibit the production or action of TNF are thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1. Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (A) ##STR2## in which Z is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing such structures are given below.
The following patent publications disclose hydroxamic acid- and/or carboxylic acid-based MMP inhibitors:
U.S. Pat. No. 4,599,361 (Searle) PA1 EP-A-2321081 (ICI) PA1 EP-A-0236872 (Roche) PA1 EP-A-0274453 (Bellon) PA1 WO 90/05716 (British Biotech) PA1 WO 90/05719 (British Biotech) PA1 WO 91/02716 (British Biotech) PA1 WO 92/09563 (Glycomed) PA1 U.S. Pat. No. 5,183,900 (Glycomed) PA1 U.S. Pat. No. 5,270,326 (Glycomed) PA1 WO 92117460 (SB) PA1 EP-A-0489577 (Celltech) PA1 EP-A-0489579 (Celltech) PA1 EP-A-0497192 (Roche) PA1 U.S. Pat. No. 5256657 (Sterling) PA1 WO 92/13831 (British Biotech) PA1 WO 92/22523 (Research Corp) PA1 WO 93109090 (Yamanouchi) PA1 WO 93/09097 (Sankyo) PA1 WO 93/20047 (British Biotech) PA1 WO 93/24449 (Celltech) PA1 WO 93124475 (Celltech) PA1 EP-A-0574758 (Roche) PA1 EP-A-0575844 (Roche) PA1 WO 94/02446 (British Biotech) PA1 WO 94/02447 (British Biotech) PA1 WO 94/21612 (Otsuka) PA1 WO 94/21625 (British Biotech) PA1 WO 94124140 (British Biotech) PA1 WO 94/25434 (Celltech) PA1 WO 94/25435 (Celltech PA1 WO 95/04033 (Celltech) PA1 WO 95/04735 (Syntex) PA1 WO 95/04715 (Kanebo) PA1 WO 95/09841 (British Biotech) PA1 WO 95/12603 (Syntex) PA1 WO 95/19956 (British Biotech) PA1 WO 95/19957 (British Biotech) PA1 WO 95/19961 (British Biotech) PA1 WO 95/19965 (Glycomed) PA1 WO 95123790 (SB) PA1 (a) one or more substituents independently selected from hydroxyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6)alkyl, -(C.sub.1 -C.sub.6)alkyl-CO.sub.2 (C.sub.1 -C.sub.6)alkyl, --CONH.sub.2, --CONH(C.sub.1 -C.sub.6)alkyl, --CON((C.sub.1 -C.sub.6)alkyl).sub.2, --CHO, --CH.sub.2 OH, --(C.sub.1 -C.sub.4)perfluoroalkyl, --O(C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, --SO(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 (C.sub.1 -C.sub.6)alkyl, --NO.sub.2, --N H.sub.2, --NH(C.sub.1 -C.sub.6)alkyl, --N((C.sub.1 -C.sub.6)alkyl).sub.2, or --NHCO(C.sub.1 -C.sub.6)alkyl, or PA1 (b) a group selected from (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, phenyl, benzyl, heteroaryl or heteroarylmethyl any of which groups may be optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, carboxyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl or --S(C.sub.1 -C.sub.6)alkyl; and PA1 --CH(C.sub.1 -C.sub.4 perfluoroalkyl).sub.2 ; PA1 --C(C.sub.1 -C.sub.4 perfluoroalkyl).sub.3 ; or PA1 --C(C.sub.1 -C.sub.6 alkyl).sub.2 R.sup.11 or a 3 to 8 membered cycloalkyl group substituted by (C.sub.1 -C.sub.6)alkyl or R.sup.11 at the alpha-position, wherein